It is well known that, in modern society, obesity or an excessive accumulation of body fat is involved in the development of diabetes mellitus, hyperlipidemia, hypertension, and atherosclerotic diseases inclusive of angina pectoris and myocardial infarction. With obesity, not only genetic factors but also environmental factors are associated.
Recently, leptin and many other obesity-related genes have been isolated from animal models. While the group of these genes thus isolated is suspected to be involved in the establishment of obesity in man, various environmental factors such as the excessive food intake and insufficient physical exercise by contemporary man are also considered to be playing a crucial role in the development of diabetes mellitus and atherosclerosis via fat storage.
Not only the search for obesity-related genes but also the approach toward elucidation of the specific genes expressed in adipose tissues under overnutrition and of the influences of such gene transcripts on the individual seem to be of remarkable significance for expatiation of the etiologies of said diseases and establishment of relevant therapeutic modalities.
The object of this invention is to cast light on the obesity-related genes and their expression products which should be useful for elucidation of the pathogenesis of various obesity-related diseases, particularly atherosclerotic diseases such as angina pectoris, myocardial infarction, etc., and establishment of pertinent therapeutic modalities and to establish therapeutic and diagnostic methods for the diseases by utilizing such genes and expression products.
The inventors have conducted intensive studies for accomplishing the above object and made it clear previously that accumulation of fat, particularly visceral fat in the abdominal cavity, is closely associated with abnormal glucose tolerance, hyperlipidemia and hypertension. Furthermore, through large-scale sequencing analyses of the genes expressed in adipose tissue, they elucidated that many secretory protein genes have been expressed in adipose tissue and that, particularly in visceral fat, the expression of various bioactive substance genes can be observed. In addition to the cloning of those known genes, the inventors succeeded in cloning an adipose tissue-specific collagen-like protein apM1 gene [Biochem. Biophys. Res. Commun., 221, 286-289 (1996)].
This apM1 gene was found to be coding for the secretory protein (apM1) consisting of 244 amino acid residues, contain a 66-residue collagen-like motif (G-X-Y), and have homology with the C1q subcomponent of the complement system and collagen X and VII. However, the physiological function of this gene and its expression product apM1 remained to be known.
In the ensuring research, the inventors made a series of investigations in regard to the expression of said apM1 gene by the genetic engineering technique, preparation of an antibody against the expression product apM1, establishment of an apM1 assay system utilizing said antibody, and relationship of the blood apM1 concentration determined by using said assay system to the body fat distribution or various diseases. The research led to the novel finding, inter alia, that apM1 has smooth muscle growth inhibitory activity and that the blood apM1 concentration faithfully reflects the atherosclerotic change.
Furthermore, the inventors obtained the novel finding that apM1 is effective in the prevention and treatment of post-angioplasty restenoses, such as restenosis after percutaneous transluminal coronary angioplasty (PTCA) using a stent, and for that matter, in the prophylaxis and therapy of atherosclerotic diseases accompanied by angiopathy, such as angina pectoris and myocardial infarction. This invention has been developed on the basis of the above finding.